The spread of antibiotic resistance in pathogens such as the “ESKAPE” pathogens, (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter species) has made the treatment of infections, especially skin and soft-tissue infections, increasingly difficult (H. Boucher, et al., Clin Infect Dis. (2009) 48 (1): 1-12.).
For example, one of the persistent problems of burn wound care is the development of microbial infections. Humans live not in a sterile environment but in a symbiotic relationship with bacteria and other microbes. The intact skin and mucosal surface act to maintain a delicate balance between our tissues and the bacterial populations. Any breach in the skin or mucosal barriers alters this balance and thus has the potential to initiate infections by allowing bacteria to gain access to the underlying tissues and achieve critical numbers. One of the major treatment goals of a burn surgeon is to prevent infections and, if contamination occurs, the goal is to reduce the microbial contamination below the critical numbers required to initiate and spread infections. With the discovery of antibiotics, burn wound infections appeared to be under control. However, it has been discovered that bacteria are able to, and indeed have, overcome the antibiotics through development of resistance. Emergence of resistant strains of bacteria has become the major source of many hospital-based infections and has posed a major clinical dilemma to burn surgeons.
The problem of antibiotic resistance affects all kinds of bacterial infections, including but not limited to infections of the skin and soft-tissues. There are many examples of the rampant rise in antibiotic resistance in pathogenic organisms. In one hospital in Corpus Christi, Tex., community-acquired methicillin-resistant Staphylococcus aureus (MRSA), most often seen in skin and soft-tissue infections, slowly increased from 3% in 1990 to 10% in 1999 and then rapidly increased over a 4-year period to 62% in 2003 (Goodman, J Clin Invest 114, 1181 (2004)). In a Miami hospital, P. aeruginosa resistance to quinolones in leg ulcers increased from 19% in 1992 to 56% in 2001 (Valencia et al., J Am Acad Dermatol 50, 845-9 (2004)). There is no debate in the field; new treatments are needed to control these infections.
Prophylactic use of antibacterial agents such as silver nitrate, silver sulfadiazine (Silverdene, Thermazine, Flamazine) and mafenide acetate (Sulfamylon) has become the standard of care to reduce bacterial colonization in wounds such as burn wounds. However, these agents have limitations. For example, Silverdene has been shown to retard wound healing and cannot be used in patients who are allergic to sulfa drugs. The metabolic products of Sulfamylon are potent inhibitors of carbonic anhydrase and therefore can cause metabolic acidosis. Use of this compound is particularly contraindicated in patients who have suffered inhalation injury and those who developed sepsis.
Other antimicrobial agents that are used to prevent or reduce bacterial colonization are Gentamicin sulfate, Bacitracin, and Nitrofurantoin. Unfortunately constant use of these antimicrobial agents results in the emergence of resistant strains of the offending bacteria.
Despite the acceptance of these antimicrobial strategies as standard of care in the treatment of burn patients, development of drug resistant bacterial infections continues to pose significant clinical problems in patients (e.g., critically injured burn patients or diabetic patients with chronic ulcers) during prolonged hospitalization.
Thus, a great need exists to develop alternative strategies of antimicrobial treatment. In particular, treatments are needed that can address and effectively kill or attenuate drug-resistant microorganisms.